基于N6-甲基腺苷和免疫微环境相关基因的乳腺癌症亚型鉴定和预后模型的建立-动脉网

Identifying subtypes and developing prognostic models based on N6-methyladenosine and immune microenvironment related genes in breast cancer

Nature 等信源发布 2024-07-18 12:30

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AbstractBreast cancer (BC) is the most prevalent cancer in women globally. The tumor microenvironment (TME), comprising epithelial tumor cells and stromal elements, is vital for breast tumor development. N6-methyladenosine (m6A) modification plays a key role in RNA metabolism, influencing its various aspects such as stability and translation.

摘要乳腺癌（BC）是全球女性中最普遍的癌症。包括上皮肿瘤细胞和基质成分的肿瘤微环境（TME）对于乳腺肿瘤的发展至关重要。N6-甲基腺苷（m6A）修饰在RNA代谢中起关键作用，影响其稳定性和翻译等各个方面。

There is a notable link between m6A methylation and immune cells in the TME, although this relationship is complex and not fully deciphered. In this research, BC expression and clinicopathological data from TCGA were scrutinized to assess expression profiles, mutations, and CNVs of 31 m6A genes and immune microenvironment-related genes, examining their correlations, functions, and prognostic impacts.

TME中m6A甲基化与免疫细胞之间存在显着联系，尽管这种关系很复杂且尚未完全破译。在这项研究中，仔细检查了来自TCGA的BC表达和临床病理数据，以评估31个m6A基因和免疫微环境相关基因的表达谱，突变和CNV，检查它们的相关性，功能和预后影响。

Lasso and Cox regression identified prognostic genes for constructing a nomogram. Single-cell analyses mapped the distribution and patterns of these genes in BC cell development. We investigated associations between gene-derived risk scores and factors like immune infiltration, TME, checkpoints, TMB, CSC indices, and drug response.

Lasso和Cox回归确定了用于构建列线图的预后基因。单细胞分析绘制了这些基因在BC细胞发育中的分布和模式。我们调查了基因衍生风险评分与免疫浸润，TME，检查点，TMB，CSC指数和药物反应等因素之间的关联。

As a complement to computational analyses, in vitro experiments were conducted to confirm these expression patterns. We included 31 m6A regulatory genes and discovered a correlation between these genes and the extent of immune cell infiltration. Subsequently, a 7-gene risk score was generated, encompassing HSPA2, TAP1, ULBP2, CXCL1, RBP1, STC2, and FLT3.

作为计算分析的补充，进行了体外实验以确认这些表达模式。。随后，产生了7个基因的风险评分，包括HSPA2，TAP1，ULBP2，CXCL1，RBP1，STC2和FLT3。

It was observed that the low-risk group exhibited better overall survival (OS) in BC, with higher immune scores but lower tumor mutational burden (TMB) and cancer stem cell (CSC) indices, as well as lower IC50 values for commonly used drugs. To enhance clinical applicability, age and stage were incorporated into the risk score, and a more comprehensive nomog.

据观察，低风险组在BC中表现出更好的总生存期（OS），免疫评分较高，但肿瘤突变负荷（TMB）和癌症干细胞（CSC）指数较低，常用药物的IC50值较低。为了提高临床适用性，将年龄和分期纳入风险评分，并提供更全面的nomog。

IntroductionBreast cancer (BC) is the most common malignant tumor among women worldwide. Approximately one in every eight women globally is diagnosed with BC ranking it as the second leading cause of death among female cancers1,2,3. This is a complex and diverse disease characterized by the uncontrolled proliferation and growth of abnormal cells in breast tissue.

简介乳腺癌（BC）是全球女性中最常见的恶性肿瘤。全球大约每八名女性中就有一名被诊断患有BC，将其列为女性癌症中第二大死亡原因1,2,3。这是一种复杂多样的疾病，其特征是乳腺组织中异常细胞的不受控制的增殖和生长。

Currently, the main clinical strategies for treating BC include mastectomy, radiotherapy, chemotherapy, endocrine therapy, and targeted therapies such as immune checkpoint inhibitors (ICIs) and antibody drug conjugates (ADCs)4,5,6,7.In cancer research, the “Tumor Microenvironment” (TME) is recognized as a critical factor in breast tumor progression.

目前，治疗BC的主要临床策略包括乳房切除术，放疗，化疗，内分泌治疗和靶向治疗，如免疫检查点抑制剂（ICIs）和抗体-药物偶联物（ADCs）4,5,6,7。在癌症研究中，“肿瘤微环境”（TME）被认为是乳腺肿瘤进展的关键因素。

It encompasses a complex interplay of epithelial tumor cells, immune cells like regulatory T cells (Tregs), myeloid-derived suppressor cells, and B cells, along with extracellular matrix, cancer-associated fibroblasts, blood vessels, and adipocytes. This intricate network is essential for understanding and combating breast cancer8.

它包括上皮肿瘤细胞，免疫细胞如调节性T细胞（Tregs），髓源性抑制细胞和B细胞以及细胞外基质，癌症相关成纤维细胞，血管和脂肪细胞的复杂相互作用。这个复杂的网络对于理解和对抗乳腺癌至关重要8。

Given the integral role of the Tumor Microenvironment (TME) in cancer study, immunotherapy, particularly with immune checkpoint inhibitors (ICIs), is gaining prominence in clinical cancer treatment for its notable therapeutic benefits9,10. The emergence of ICIs represents a therapeutic revolution of the past decade, with immunotherapy being an effective treatment strategy for a variety of tumors.

鉴于肿瘤微环境（TME）在癌症研究中的不可或缺的作用，免疫治疗，特别是免疫检查点抑制剂（ICIs），在临床癌症治疗中因其显着的治疗益处而日益突出9,10。ICI的出现代表了过去十年的治疗革命，免疫疗法是多种肿瘤的有效治疗策略。

The mechanism of action of ICIs is based on the activation of the immune system, capable of modulating T lymphocytes and targeting immune checkpoints, such as Programmed Cell Death Protein 1 (PD-1), Programmed Cell Death Ligand 1 (PD-L1), and Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4). As monotherapy or in combination with other antican.

。作为单一疗法或与其他抗癌药物联合使用。

Data availability

数据可用性

Publicly available datasets were analyzed in this study. This data can be found here: https://portal.gdc.cancer.gov/, https://www.ncbi.nlm.nih.gov/geo/, https://www.cbioportal.org and https://www.cancer.gov/ccg/research/genome-sequencing/tcga.

本研究分析了公开可用的数据集。这些数据可以在这里找到：https://portal.gdc.cancer.gov/，https://www.ncbi.nlm.nih.gov/geo/，https://www.cbioportal.org和https://www.cancer.gov/ccg/research/genome-sequencing/tcga.

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Download referencesFundingThis work is supported by National Natural Science Foundation of China (No. 82203122), and Shaanxi Key Research and Development Program (No.2021SF-203).Author informationAuthor notesThese authors contributed equally: Lizhao Wang and Jianpeng Li.Authors and AffiliationsDepartment of Breast Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, 710061, Shaanxi, ChinaLizhao Wang, Heyan Chen, Ligang Niu, Jianjun He & Ru WangDepartment of Urology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, ChinaJianpeng LiDepartment of Hematology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, ChinaNan MeiAuthorsLizhao WangView author publicationsYou can also search for this author in.

下载参考文献资助这项工作得到了国家自然科学基金（No.82203122）和陕西省重点研究发展计划（No.2021SF-203）的支持。作者信息作者注意到，这些作者做出了同样的贡献：王立钊和李建鹏。作者和附属机构西安交通大学第一附属医院乳腺外科，西安雁塔西路277号，陕西710061，中国王立钊，陈何燕，牛立刚，何建军和王汝西安交通大学第一附属医院泌尿外科，西安710061，中国陕西省西安710061西安交通大学第一附属医院血液科您也可以在中搜索此作者。

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PubMed Google ScholarContributionsR.W., J.H., J.L. and L.W. performed experiments, data analysis, and article writing. L.W., H.C. and N.M. assist the performance of experiments and data analysis. L.W. and H.C provided software and technical assistance. R.W. and L.N. provided funds to support this study. R.W.

PubMed谷歌学术贡献。W、，J.H.，J.L.和L.W.进行了实验，数据分析和文章写作。五十、 W.，H.C.和N.M.协助进行实验和数据分析。五十、 W.和H.C提供了软件和技术援助。R、 W.和L.N.提供资金支持这项研究。R。W。

and L.W. designed and directed the whole processes. All authors approved the final manuscript.Corresponding authorsCorrespondence to.

L.W.设计并指导了整个过程。所有作者都批准了最终稿件。通讯作者通讯。

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Reprints and permissionsAbout this articleCite this articleWang, L., Li, J., Mei, N. et al. Identifying subtypes and developing prognostic models based on N6-methyladenosine and immune microenvironment related genes in breast cancer.

转载和许可本文引用本文Wang，L.，Li，J.，Mei，N。等人基于N6-甲基腺苷和免疫微环境相关基因在乳腺癌中鉴定亚型并开发预后模型。

Sci Rep 14, 16586 (2024). https://doi.org/10.1038/s41598-024-67477-wDownload citationReceived: 14 May 2024Accepted: 11 July 2024Published: 18 July 2024DOI: https://doi.org/10.1038/s41598-024-67477-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsBreast cancerN6-methyladenosineImmune microenvironmentGene signaturePrognosis

关键词乳腺癌6-甲基腺苷免疫微环境基因特征预测

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